BG63864B1 - Antimycotic gel having high degree of the active substance release - Google Patents
Antimycotic gel having high degree of the active substance release Download PDFInfo
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Abstract
Description
Област на техникатаTechnical field
Настоящото изобретение се отнася до антимикотично действащ препарат за топично прилагане с висока степен на освобожда, 10 ване на активно вещество във форма на гел, който съдържа най-малко едно антимикотично активно вещество от класа на хидроксипиридона и най-малко едно хидрофилно гелообразуващо средство.The present invention relates to an antimycotically active preparation for topical application with a high release rate, 10 g of active ingredient in gel form, which contains at least one antimycotic active substance in the class of hydroxypyridone and at least one hydrophilic gel-forming agent.
Предшестващо състояние на техникатаBACKGROUND OF THE INVENTION
За топично лечение на микози, преди всичко микози на кожата, са известни различни готови форми от производни на хид- 20 роксипиридон като разтвори, мази и прахове. Едно оптимално третиране на кожни микози с досега известните готови форми, съдържащи хидроксипиридони, поради различни основания, не е неограничено възможно. 25For the topical treatment of mycoses, especially mycoses of the skin, various formulations of hydroxoxypyridone derivatives, such as solutions, ointments and powders, are known. An optimal treatment of skin mycoses with the hitherto known formulations containing hydroxypyridones for various reasons is not unlimitedly possible. 25
Течните форми за топично прилагане обхващат най-общо бистри водни или водно-алкохолни разтвори. Те или се нанасят по повърхността на кожата, или се използват за миене или къпане. Особено приложение намират за някои кожни области, които са покрити с гъсто окосмяване, тъй като за тези области не са подходящи мази или прахове. Освен това те са удачни за такива места по кожата, за които други лекарствени форми, поради козметични основания, не се употребяват охотно, например по лицето или по силно движещи се места по тялото (напр. лакът, коляно и т.н.).Liquid forms for topical administration generally comprise clear aqueous or water-alcoholic solutions. They are either applied to the surface of the skin or used for washing or bathing. They are particularly useful for some skin areas that are covered with dense hair, as these areas are not suitable ointments or powders. In addition, they are suitable for skin areas for which other dosage forms, for cosmetic reasons, are not readily used, for example on the face or in highly moving areas of the body (eg elbow, knee, etc.).
Скоростта на освобождаване на активното вещество от разтворите е най-общо висока, тъй като след употреба чрез изпаряване на съставната част на носителя възниква силен спад на концентрацията между препарата и кожата, което всъщност довежда до високо приемане на активно вещество чрез кожата и с това до висока ефективност.The rate of release of the active substance from the solutions is generally high since, after use by evaporation of the constituent of the carrier, there is a sharp decrease in the concentration between the preparation and the skin, which in fact leads to a high uptake of the active substance by the skin, and thereby high efficiency.
С оглед на техните приложни свойства, разтворите се оценяват по-скоро като по-малко благоприятни, тъй като заради тяхното течно агрегатно състояние, особено в областта на лицето, трудно се борави с тях и някои целени нанасяния в ограничени области на кожата не са възможни.In view of their applied properties, the solutions are considered rather less favorable, because of their liquid state, especially in the facial area, it is difficult to handle them and some targeted application in limited areas of the skin is not possible .
Мази или полутвърди лекарствени форми са готови форми, които най-общо могат да се нанасят в температурни граници между стайна температура и температурата на кожата и поради това се разграничават от течните форми и тези с твърд характер. На база свойствата на главния носител под мази най-общо се разбират безводни маслени или състоящи се от маслена и водна фаза емулсии, които са стабилизирани с емулгатор.Ointments or semi-solid dosage forms are formulations that can generally be applied within temperature ranges between room temperature and skin temperature and are therefore distinguished from liquid forms and those of a solid nature. Based on the properties of the main carrier, ointments generally mean anhydrous oil-based or oil-water phase emulsions that are stabilized with an emulsifier.
Въз основа на полутвърдата консистенция мазите - обратно на разтворите - позволяват да се нанасят върху точно определено ограничено място на кожата. В зависимост от съдържанието на маслената съставна част, освобождаването на липофилните производни на хидроксипиридона от съставните части на мазите е силно затруднено. Резултатът от лечението след прилагане на мазите освен това се влошава от това, че обикновено мазите не оставят върху кожата труднопочистващ се филм. Нанесеният продукт може при съприкосновение с дрехите или бельото лесно да бъде отстранен и поради това повече не е на разположение за резултат на лечение.Based on the semi-solid consistency, the ointments - back to the solutions - allow them to be applied to a specific restricted area of the skin. Depending on the content of the oily component, the release of the lipophilic hydroxypyridone derivatives from the ointment components is very difficult. The result of post-ointment treatment is further exacerbated by the fact that ointments generally do not leave a film that is difficult to clean on the skin. The applied product can be easily removed when in contact with clothes or underwear and is therefore no longer available for treatment.
Праховете зависят на първо място от абсорбцията на увеличената секреция и сухостта на кожата, което по-специално при лечението на кожни микози играе важна роля. Прилагането на прахообразни форми, поради практически причини е ограничено изключително върху лечението на микози по ходилата.Powders depend first and foremost on the absorption of increased secretion and dryness of the skin, which in particular plays an important role in the treatment of skin mycoses. The administration of powders for practical reasons is limited solely to the treatment of foot mycosis.
Техническа същност на изобретениетоSUMMARY OF THE INVENTION
Установено е сега, че гелни форми от производни на хидроксипиридони, които съдържат разтворител и хидрофилно гелообразуващо средство, както и обичайни помощни средства, улесняват висока степен на освобождаване на активното вещество и с това подобрено действие чрез достигане на висока концентрация на активно вещество в кожата. Формите съгласно изобретението, благодарение на тяхната полутвърда консистенция, могат лесно и насочено да се нанасят върху поразената част от кожата и освен това показват желания ефект на изсушаване, особено при лечение на микози на ходилата.It has now been found that gel forms of hydroxypyridone derivatives containing solvent and hydrophilic gel-forming agent, as well as conventional excipients, facilitate a high degree of release of the active substance and thus improved action by achieving a high concentration of active substance in the skin. The formulations according to the invention, due to their semi-solid texture, can be easily and targetedly applied to the affected part of the skin and further show the desired drying effect, especially in the treatment of foot mycosis.
Изобретението се отнася до фармацевтичен състав, съдържащ хидрофилно гелообразуващо средство, вода и съединение с формулаThe invention relates to a pharmaceutical composition comprising a hydrophilic gel-forming agent, water and a compound of formula
или физиологично приемлива сол на съединение с формула I, в която формула R1, R2 и R3 са еднакви или различни и означават водород или алкил с 1 до 4 въглеродни атома и R4 означава наситен въглеводороден остатък с 6 до 9 въглеродни атома.or a physiologically acceptable salt of a compound of formula I wherein R 1 , R 2 and R 3 are the same or different and represent hydrogen or alkyl having 1 to 4 carbon atoms and R 4 means a saturated hydrocarbon residue having 6 to 9 carbon atoms.
Предпочитан е фармацевтичен състав, при който R4 означава наситен въглеводород с 6 до 9 въглеродни атома, единият от остатъците R1 и R3 е водород, а другият е водород, метил или етил и R2 означава алкилов остатък с 1 или 2 въглеродни атома.A pharmaceutical composition is preferred wherein R 4 represents a saturated hydrocarbon of 6 to 9 carbon atoms, one of the residues R 1 and R 3 is hydrogen and the other is hydrogen, methyl or ethyl and R 2 means an alkyl residue of 1 or 2 carbon atoms .
Особено предпочитан е фармацевтичен състав, при който съединение с формула I в позиция R4 има цикличен остатък.Particularly preferred is a pharmaceutical composition wherein the compound of formula I at position R 4 has a cyclic moiety.
Предпочитан е и фармацевтичният състав, при който R4 означава циклохексилов остатък или -CH^CHiCHp-CHj-CiCHPj.Also preferred is a pharmaceutical composition wherein R 4 is a cyclohexyl moiety or -CH 2 CH 1 CH 5 -CH 2 -C 1 CH 2 P 2.
“Наситен” тук означава такъв остатък, който не съдържа никакви алифатни сложни връзки, също никакви етиленови или ацетиленови връзки."Saturated" here means a residue which does not contain any aliphatic complex bonds, nor any ethylene or acetylene bonds.
Като подходящи съединения с формула I могат да се назоват 1-хидрокси-4-метил-6-норм.-хексил-, -6-изохексил-, -6норм.-хептил или -6-изохептил-2-пиридон; 1-хидрокси-4-метил-6-октил- или -6-изооктил-2-пиридон; по-специално 1-хидрокси-4метил-6-(2,4,4-триметилпентил)-2-пиридон; 1-хидрокси-4-метил-6-циклохексил-2-пиридон; I-хидрокси-4-метил-6-циклохексилметил- или -6-циклохексилетил-2-пиридон, при което циклохексиловият остатък може да носи и метилов остатък; 1-хидрокси-4-метил-6(2-бицикло [2,2,1 ] хептил) -2-пиридон; 1 -хидрокси-3,4-диметил-6-бензил- или -6-диметилбензил-2-пиридон; и 1 -хидрокси-4-.метил6-( β-фенилетил)-2-пиридон.Suitable compounds of formula I may be referred to as 1-hydroxy-4-methyl-6-norm-hexyl, -6-isohexyl, -6-nor-heptyl or -6-isoheptyl-2-pyridone; 1-hydroxy-4-methyl-6-octyl- or -6-isooctyl-2-pyridone; in particular 1-hydroxy-4methyl-6- (2,4,4-trimethylpentyl) -2-pyridone; 1-hydroxy-4-methyl-6-cyclohexyl-2-pyridone; I-hydroxy-4-methyl-6-cyclohexylmethyl- or -6-cyclohexylethyl-2-pyridone, wherein the cyclohexyl moiety may also carry a methyl moiety; 1-hydroxy-4-methyl-6 (2-bicyclo [2,2,1] heptyl) -2-pyridone; 1-hydroxy-3,4-dimethyl-6-benzyl- or -6-dimethylbenzyl-2-pyridone; and 1-hydroxy-4-methyl-6- (β-phenylethyl) -2-pyridone.
Изобретението се отнася и до използване на фармацевтичния състав за приготвяне на лекарствено средство и профилактика на кожни микози.The invention also relates to the use of the pharmaceutical composition for the preparation of a medicament and the prevention of skin mycoses.
С лекарственото средство съгласно настоящото изобретение при третиране на кожни микози се достига решително излекуване. Лекарственото средство съгласно изобретението е подходящо също и за профилак10 тично прилагане срещу кожни микози.With the medicament of the present invention, a definitive cure is achieved in the treatment of skin mycoses. The drug of the invention is also suitable for prophylactic administration against skin mycoses.
Съдържанието на съединението с формула 1 във фармацевтичния състав съгласно изобретението зависи от структурата на всяко едно съединение с формула I и тяхното ос15 вобождаване от гела, от проникването им в кожата и противомикробните им свойства.The content of the compound of formula I in the pharmaceutical composition according to the invention depends on the structure of each compound of formula I and their axis of gel release, their penetration into the skin and their antimicrobial properties.
Във фармацевтичния състав съгласно изобретението съединението с формула I найобщо се съдържа в количество от 0,05-2% 20 тегл., за предпочитане 0,1-1% тегл.In the pharmaceutical composition according to the invention, the compound of formula I is generally contained in an amount of 0.05-2% by weight, preferably 0.1-1% by weight.
Като гелообразуващо средство се имат предвид природни субстанции като желатин, пектин, караген, агар, трагант и алгинат, полусинтетично гелообразуващо средство като 25 целулозен етер (метилцелулоза, етилцелулоза, хи д роксиетил целулоза, хидроксип роп илцелулоза, натриева карбокси метил целулоза), производно на нишесте и производно на пектин, както и напълно синтетично гелообра30 зуващо средство като полиакрилат, полиметакрилат, поливинилов алкохол и поливинилпиролидон. Особено подходящи са полиакрилати. Те се използват в количество 0,3-2,0 тегл.ч. на 100 тегл.ч. от крайния продукт.Natural gels such as gelatin, pectin, carrageen, agar, tragacanth and alginate, a semi-synthetic gel-forming agent such as 25 cellulose ether (methylcellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropylcellulose carboxylic acid, cellulose, cellulose, carboxylic acid, cellulose, carboxylic acid, cellulose) starch and pectin derivative as well as fully synthetic gel-forming agents such as polyacrylate, polymethacrylate, polyvinyl alcohol and polyvinylpyrrolidone. Polyacrylates are particularly suitable. They are used in an amount of 0.3-2.0 parts by weight. per 100 parts by weight from the final product.
Като разтворител се използва вода и също всички смесващи се с вода разтворители. Имат се предвид например алкохол като етанол или изопропилов алкохол, както и пропиленгликол и диметилсулфоксид. При по40 лучаването на формите съгласно изобретението могат да се използват един или повече разтворители.Water and all miscible solvents are used as the solvent. For example, alcohol, such as ethanol or isopropyl alcohol, as well as propylene glycol and dimethyl sulfoxide are contemplated. In the preparation of the forms according to the invention, one or more solvents may be used.
Като допълнителни разтворители за формата съгласно изобретението са подхо45 дящи: бензилов алкохол, 2-октилдодеканол, адипат, пропиленгликол и глицерин. Тези разтворители се съдържат във формата съгласно изобретението от 1 до 15% тегл.Suitable solvents for the formulation according to the invention are benzyl alcohol, 2-octyldodecanol, adipate, propylene glycol and glycerol. These solvents are present in the formulation of the invention from 1 to 15% by weight.
Като други помощни средства са под50 ходящи емулгатори, омокрящи средства и разстилащи средства.Other adjuvants include suitable emulsifiers, wetting agents and spreading agents.
Получаването на формите се извършва по познат начин чрез смесване на компонентите и необходимата по-нататък, приспособена за съответната форма преработка.The preparation of the molds is accomplished in a known manner by mixing the components and the necessary further adapted for the respective form of processing.
Примери за изпълнение на изобретениетоExamples of carrying out the invention
Настоящото изобретение се обяснява по-подробно със следващите примери, които не го ограничават. Ако не е посочено друго, количествата са тегловни.The present invention is explained in more detail with the following non-limiting examples. Unless otherwise indicated, the quantities are by weight.
Пример 1. Форма съгласно изобретението със следния състав в %:Example 1. Formulation according to the invention with the following composition in%:
Полиетилен (20)сорбитанмоностеарат 3,50Polyethylene (20) sorbitan monostearate 3.50
Сорбитанмоностеарат 1,50Sorbitan monostearate 1.50
Деминерализирана вода 49,00.Demineralized water 49,00.
Пример 5. Изследване на активността.Example 5. Activity Study.
Изпитване на освобождаване на активното вещество от фармацевтична форма съгласно изобретението в пенетрационен модел с изрязана свинска кожа.Release test of the active substance of the pharmaceutical formulation according to the invention in a pig-skin cut-off model.
Изпитването за освобождаване на активното вещество от средствата съгласно изобретението се осъществява на пенетрационен модел с изрязана свинска кожа. При това се правят индиректни изводи върху определянето на дълбочината на проникване посредством микробиологичен метод на определяне за освобождаването на активното вещество от средствата съгласно изобретението.The test for the release of the active substance from the agents according to the invention is carried out on a penetrating model with excised pork skin. Indirect conclusions are thus made on the determination of the penetration depth by a microbiological method of determining the release of the active substance from the agents according to the invention.
От свине за клане преди попарването на убитите животни се изрязват по-големи повърхности от кожата на гърба, увиват се с влажна хартия и пластмасово фолио и до опита се замразяват дълбоко при -20°С.Before slaughtering the slaughtered pigs, larger surfaces are cut from the back skin, wrapped in moist paper and plastic wrap, and deep frozen at -20 ° C until the experiment.
Кожната повърхност преди опита се освобождава от мастната тъкан, обръсва се и се обработва с изопропанол за дезинфекция в продължение на 60 min. За всеки опит се използва отделно парче кожа (2x3 cm). Кожната повърхност се обработва с препарати, съдържащи различни съединения с формула I. След края на различните времена на въздействие (0,5, 1 и 4 h) продуктите се отстраняват от кожната повърхност чрез измиване. За да се изследват различните възможности за проникване на активните вещества, съответно различните възможности за освобождаване от препаратите, парчетата кожа се почистват на по три, едно до друго разположени ивици с Tesafilm 2х, 6х и 10х. Всяка ивица след това се инокулира 10х точкообразно със суспензия от Trichophyton mentagrophytes 100/25 (около 200 микроконидии за точка на заразяване). След това парчетата кожа се инкубират върху воден агар с добавка на пеницилин, стрептомицин и циклохексимид 7 дни при 28°С. Като се започне от четвъртия ден на инкубация се прави ежедневно макроскопско отчитане.The skin surface prior to the test was released from the adipose tissue, shaved and treated with isopropanol for disinfection for 60 min. A separate piece of leather (2x3 cm) is used for each experiment. The skin surface is treated with preparations containing various compounds of formula I. After the end of the different exposure times (0.5, 1 and 4 h), the products are removed from the skin surface by washing. In order to investigate the different penetration possibilities of the active substances, respectively the different release options from the preparations, the pieces of skin are cleaned in three, side by side, strips of Tesafilm 2x, 6x and 10x. Each strip was then inoculated 10x with a suspension of Trichophyton mentagrophytes 100/25 (about 200 microconidia per infection point). The skin fragments were then incubated on aqueous agar with the addition of penicillin, streptomycin and cycloheximide for 7 days at 28 ° C. Beginning with the fourth day of incubation, daily macroscopic reading is performed.
РезултатThe result
След време на въздействие 4 h на съдържащите активно вещество гелни форми съгласно примери 1-3, парчетата кожа по всички изрезки макроскопски не съдържат гъ- 5 би обратно на съответните плацебо препарати. Времето на въздействие 4 h за препарати мази, съдържащи активно вещество, които не са съгласно изобретението по пример 4 и които са получени съгласно нивото на 10 техниката, не е достатъчно, за да се убият макроконидиите върху инокулираните сегменти.After an exposure time of 4 h of the active ingredient gel formulations according to Examples 1-3, the skin fragments macroscopically did not contain any gaps in the corresponding placebo preparations. The exposure time of 4 h for preparations of ointments containing the active substance not in accordance with the invention of Example 4 and obtained according to the prior art is not sufficient to kill the macroconidia on the inoculated segments.
Патентни претенцииClaims
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DE19639816A DE19639816A1 (en) | 1996-09-27 | 1996-09-27 | Antifungal agents with high drug release |
PCT/EP1997/005068 WO1998013042A1 (en) | 1996-09-27 | 1997-09-16 | Antimycotic gel with high active substance release |
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1996
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- 1997-09-16 CZ CZ19991073A patent/CZ291170B6/en not_active IP Right Cessation
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- 1997-09-16 KR KR10-1999-7002561A patent/KR100457850B1/en not_active IP Right Cessation
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- 1997-09-16 AT AT97909278T patent/ATE216882T1/en active
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- 1997-09-16 US US09/068,894 patent/US7018656B2/en not_active Expired - Fee Related
- 1997-09-16 JP JP10515221A patent/JP2001501609A/en active Pending
- 1997-09-16 HU HU9903804A patent/HU228297B1/en unknown
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- 1997-09-25 AR ARP970104430A patent/AR008858A1/en not_active Application Discontinuation
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